Hyperandrogenism in women of reproductive age is a common clinical problem. For the vast majority of hyperandrogenic women no specific etiologic cause can be identified. These cases are often diagnosed as having the "polycystic ovary syndrome". A unique opportunity to identify a specific molecular cause of the polycystic ovary syndrome is provided by the recent clinical observation that hyperinsulinemia is commonly associated with hyperandrogenism. The objective of this research proposal is to investigate the effects of insulin and insulin-like growth factors (IGFs) on ovarian steroidogenesis. In particular, the effects of insulin and IGFs on androgen production in the thecal and stromal compartments of the ovary will be examined in detail. Preliminary findings from our laboraroty which support the hypothesis that insulin stimulates gonadal androgen production include the following: 1) insulin stimulated dihydrotestosterone, testosterone, and androstenedione production, but not progesterone production in long-term incubations of minced porcine theca; 2) insulin stimulated the metabolism of testosterone to dihydrotestosterone in long-term incubations of minced human theca and stoma; and 3) incubations of minced ovaries from human-chorionic-gonadotropin hCG-treated lean (ob/+ or +/+) mice. These results suggest that insulin may be a major regulator of gonadal androgen production. The effects of insulin on ovarian androgen production will be further characterized by the following experients: 1) determination of the species specificity of the insulin effect on ovarian androgen production; 2) determination of the ovarian compartment most sensitive to the effects of insulin (theca, stoma or granulosa cells); 3) analysis of the effects of insulin-like growth factors (IGFs) (IGF-I, IGF-II, relaxin) on ovarian androgen synthesis; 4) analysis of the binding characteristics of insulin and IGFs to the insulin receptor present in ovarian theca and stroma; 5) analysis of the effects of insulin and IGFs on specific enzymes of thecal androgen biosynthesis (5alpha-reductase, 17Beta-hydroxysteroid dehydrogenase, 17alpha-hydroxylase, and 3Beta-hydroxysteroid dehydrogenase); and 6) investigation of the possible linkage of the ovarian insulin receptor to a tyrosine-specific protein kinase.